title: Thielavins A, J and K: α-Glucosidase inhibitors from MEXU 27095, an endophytic fungus from Hintonia latiflora.
abstract: Bioassay-guided fractionation of the bio-active organic extract obtained from solid-media culture of MEXU 27095, an endophytic fungus isolated from the Mexican medicinal plant Hintonia latiflora (Rubiaceae), led to separation of three tridepsides which were identified as thielavins A, J and K. All three compounds inhibited Saccharomyces cerevisieae α-glucosidase (αGHY) in a concentration-dependent manner with IC50 values of 23.8, 15.8, and 22.1μM, respectively. Their inhibitory action was higher than that of acarbose (IC50=545μM), used as a positive control. Kinetic analysis established that the three compounds acted as non-competitive inhibitors with ki values of 27.8, 66.2 and 55.4μM, respectively (α=1.0, 1.2, 0.7, respectively); acarbose behaved as competitive inhibitor with a ki value of 156.1μM. Thielavin J inhibited the activity of α-glucosidase from Bacillus stearothermophilus (αGHBs) with an IC50 of 30.5μM, being less active than acarbose (IC50=0. 015μM); in this case, compound (2) (ki=20.0μM and α=2.9) and acarbose (ki=0.008μM and α=1.9) behaved as non-competitive inhibitors. Docking analysis predicted that all three thielavins and acarbose bind to homologated αGHBs and to αGHY (PDB: 3A4A) in a pocket close to the catalytic site for maltose and isomaltose, respectively. The α-glucosidase inhibitory properties of thielavin K (3) were corroborated in vivo since it induced a noted antihyperglycemic action during an oral sucrose tolerance test (3.1, 10.0 and 31.6mg/kg) in normal and nicotinamide-streptozotocin diabetic mice. In addition, at a dose of 10mg/kg, it provoked a moderate hypoglycemic activity in diabetic mice.
authors.affiliation: Facultad de Química, Universidad Nacional Autónoma de México, México DF 04510, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Rivera-Chávez
authors.forename: Martín
authors.initials: M
authors.lastname: González-Andrade
authors.forename: María del Carmen
authors.initials: Mdel C
authors.lastname: González
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Glenn
authors.forename: Rachel
authors.initials: R
authors.lastname: Mata
mesh_terms: D020909:Acarbose / Q000494:pharmacology; D000818:Animals; D001203:Ascomycota / Q000737:chemistry*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D062385:Hydroxybenzoates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008800:Mexico; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D015394:Molecular Structure; D008517:Phytotherapy; D010946:Plants, Medicinal / Q000382:microbiology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019666:Rubiaceae / Q000382:microbiology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000737:chemistry / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D062385:Hydroxybenzoates; D007004:Hypoglycemic Agents; C587565:thielavin J; C587566:thielavin K; C033794:thielavin A; D000520:alpha-Glucosidases; D020909:Acarbose
keywords: Endophytic fungus; Enzymatic inhibition; Hintonia latiflora; Molecular docking; Oral sucrose tolerance test; Thielavins; Type II diabetes mellitus; α-Glucosidase